Using cutting edge technologies including next generation sequencing of laser capture microdissected formalin-fixed tissue, we are comparing the genomic and transcriptomic profiles of high grade prostate cancers (that have progressed to Gleason score 7 or higher) to indolent cancers (Gleason score 6 prostate cancers from an active surveillance cohort). We are also comparing the genomic trajectory of cancers that respond to systemic therapy to those that fail to respond. We hypothesize that a switch in the early natural history of the tumor sets an aggressive fate that can be detected early, guiding options for management and treatment.